Benzamide derivatives

ABSTRACT

Disclosed are benzamide derivatives useful in slowing the expansion of cancer cells including the killing of cancer cells and in the treatment of cancer.

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of death in the United States anddespite new breakthroughs that have led to decreased mortality, manycancers remain refractory to treatment. Additionally, typical treatmentssuch as chemotherapy, radiotherapy and surgery cause a broad spectrum ofundesirable side effects. In addition, many cancers often developresistance to current chemotherapies over time. Clearly the field is insignificant need of novel compounds and methods of slowing the expansionof cancer cells and that are useful in the treatment of cancer.

BRIEF SUMMARY OF THE INVENTION

The present invention provides among other things a compound that iseffective in slowing the growth of cancer cells.

It is an object of the invention to provide a pharmaceutical compositionthat slows the expansion of cancer cells.

It is an object of the invention to provide a pharmaceutical compositionthat kills cancer cells.

It is an object of the invention to treat cancer.

It is an object of the invention to treat cancers that are resistant tochemotherapy.

It is an object of the invention to provide a pharmaceutical compositionthat selectively targets cisplatin-resistant tumors.

The above and other objects may be achieved using devices involving acompound of formula

The group denoted by X may be any of H, halo, —C₁-C₆ alkyl, aryl, —C₃-C₇cycloalkyl or -3- to 10-membered heterocycle, any of which may beunsubstituted or substituted with one or more of the following: -halo,—C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′,N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆alkyl.

The group denoted by Y1 and Y2 may independently be any of H, —C₁-C₆alkyl, —C₃-C₇ cycloalkyl, any of which may be unsubstituted orsubstituted with one or more of the following: -halo, —C₁-C₆ alkyl,—O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R)₂, —NHC(O)R′ or—C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆ alkyl.

The group denoted by Z may be methyl, —NH2, —NHOH, or phenylene diaminegroup (III)

Examples include but need not be limited to:N-hydroxy-2-(3-methyl-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(1-phenylcyclopropanecarboxamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methyl-2-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(3-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methoxy-2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylpropanamido)thiazole-5-carboxamide;2-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxythiazole-5-carboxamide;2-(2,2-dimethyl-3-phenylpropanamido)-N-hydroxythiazole-5-carboxamide;2-(2-(4-bromophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(4-methoxy-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(3-methoxy-2-phenylpropanamido)thiazole-5-carboxamide; and 42-(2-(biphenyl-4-yl)butanamido)-N-hydroxythiazole-5-carboxamide

The above and other objects may be achieved through methods involving acompound of formula

The group denoted by X may be any of H, halo, —C₁-C₆ alkyl, aryl, —C₃-C₇cycloalkyl or -3- to 10-membered heterocycle, any of which may beunsubstituted or substituted with one or more of the following: -halo,—C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′,N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆alkyl.

The group denoted by Y1 and Y2 may independently be any of H, —C₁-C₆alkyl, —C₃-C₇ cycloalkyl, any of which may be unsubstituted orsubstituted with one or more of the following: -halo, —C₁-C₆ alkyl,—O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R)₂, —NHC(O)R′ or—C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆ alkyl.

The group denoted by Z may be methyl, —NH2, —NHOH, or phenylene diaminegroup (III)

Examples include but need not be limited to:

-   4-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxybenzamide and    N-hydroxy-4-(2-(4-methoxyphenyl)butanamido)benzamide.

The above and other objects may be achieved by methods involvingadministering an effective amount of a pharmaceutical composition thatincludes the disclosed compound and, in some aspects of the invention,one or more pharmaceutically acceptable carriers.

The above and other objects may be achieved by methods involvingadministering an effective amount of a pharmaceutical composition thatincludes the disclosed compound and, in some aspects of the invention,one or more pharmaceutically acceptable carriers.

DETAILED DESCRIPTION OF THE INVENTION

Aspects and applications of the invention presented here are describedbelow in the drawings and detailed description of the invention. Unlessspecifically noted, it is intended that the words and phrases in thespecification and the claims be given their plain, ordinary, andaccustomed meaning to those of ordinary skill in the applicable arts.Inventors are fully aware that they can be their own lexicographers ifdesired

Inventors are also aware of the normal precepts of English grammar.Thus, if a noun, term, or phrase is intended to be furthercharacterized, specified, or narrowed in some way, then such noun, term,or phrase will expressly include additional adjectives, descriptiveterms, or other modifiers in accordance with the normal precepts ofEnglish grammar. Absent the use of such adjectives, descriptive terms,or modifiers, it is the intent that the noun, term, or phrase is givenits broadest possible meaning.

Further, the inventors are fully informed of the standards andapplication of the special provisions of 35 U.S.C. §112, ¶ 6. Thus, theuse of the words “function,” “means” or “step” in the DetailedDescription or Description of the Drawings or claims is not intended tosomehow indicate a desire to invoke the special provisions of 35 U.S.C.§112, ¶ 6, to define the invention. To the contrary, if the provisionsof 35 U.S.C. §112, ¶ 6 are sought to be invoked to define theinventions, the claims will specifically and expressly state the exactphrases “means for” or “step for, and will also recite the word“function” (i.e., will state “means for performing the function of[insert function]”), without also reciting in such phrases anystructure, material or act in support of the function. Thus, even whenthe claims recite a “means for performing the function of . . . ” or“step for performing the function of . . . ,” if the claims also reciteany structure, material or acts in support of that means or step, orthat perform the recited function, then it is the clear intention of theinventors not to invoke the provisions of 35 U.S.C. §112, ¶ 6. Moreover,even if the provisions of 35 U.S.C. §112, ¶ 6 are invoked to define theclaimed inventions, it is intended that the inventions not be limitedonly to the specific structure, material or acts that are described inthe preferred embodiments, but in addition, include any and allstructures, materials or acts that perform the claimed function asdescribed in alternative embodiments or forms of the invention, or thatare well known present or later-developed, equivalent structures,material or acts for performing the claimed function. In the followingdescription, and for the purposes of explanation, numerous specificdetails are set forth in order to provide a thorough understanding ofthe various aspects of the invention. It will be understood, however, bythose skilled in the relevant arts, that the present invention may bepracticed without these specific details. In other instances, knownstructures and devices are shown or discussed more generally in order toavoid obscuring the invention.

In the following description, and for the purposes of explanation,numerous specific details are set forth in order to provide a thoroughunderstanding of the various aspects of the invention. It will beunderstood, however, by those skilled in the relevant arts, that thepresent invention may be practiced without these specific details. Inother instances, known structures and devices are shown or discussedmore generally in order to avoid obscuring the invention. In many cases,a description of the operation is sufficient to enable one to implementthe various forms of the invention. It should be noted that there aremany different and alternative configurations, devices, compositions,and technologies to which the disclosed invention may be applied. Thefull scope of the inventions is not limited to the examples that aredescribed below.

Herein the Inventors disclose a compound has with a formula of:

and a compound with the formula of

The group denoted by X may be any of H, halo, —C₁-C₆ alkyl, aryl, —C₃-C₇cycloalkyl or -3- to 10-membered heterocycle, any of which may beunsubstituted or substituted with one or more of the following: -halo,—C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′,N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆alkyl.

The group denoted by Y1 and Y2 may independently be any of H, —C₁-C₆alkyl, —C₃-C₇ cycloalkyl, any of which may be unsubstituted orsubstituted with one or more of the following: -halo, —C₁-C₆ alkyl,—O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R)₂, —NHC(O)R′ or—C(O)NHR′ groups wherein R′ may be —H or —C₁-C₆ alkyl.

The group denoted by Z may be methyl, —NH2, —NHOH, or phenylene diaminegroup (III)

A —C₁-C₆ alkyl group includes any straight or branched, saturated orunsaturated, substituted or unsubstituted hydrocarbon comprised ofbetween one and six carbon atoms. Examples of —C₁-C₆ alkyl groupsinclude, but are not limited to methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,neohexyl, ethylenyl, propylenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, acetylenyl, pentynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and3-hexynyl groups. Substituted —C₁-C₆ alkyl groups may include anyapplicable chemical moieties. Examples of groups that may be substitutedonto any of the above listed —C₁-C₆ alkyl groups include but are notlimited to the following examples: halo, —C₁-C₆ alkyl, —O—(C₁-C₆ alkyl),—OH, —CN, —COOR′, —OC(O)R′, —NHR′, N(R′)₂, —NHC(O)R′ or —C(O)NHR′groups. The groups denoted R′ above may be —H or any —C₁-C₆ alkyl.

A —C₁-C₆ alkyl group includes any straight or branched, saturated orunsaturated, substituted or unsubstituted hydrocarbon comprised ofbetween one and six carbon atoms. Examples of —C₁-C₆ alkyl groupsinclude, but are not limited to methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,neohexyl, ethylenyl, propylenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, acetylenyl, pentynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and3-hexynyl groups. Substituted —C₁-C₆ alkyl groups may include anyapplicable chemical moieties. Examples of groups that may be substitutedonto any of the above listed —C₁-C₆ alkyl groups include but are notlimited to the following examples: halo, —C₁-C₆ alkyl, —O—(C₁-C₆ alkyl),—OH, —CN, —COOR′, —OC(O)R′, —NHR′, N(R′)₂, —NHC(O)R′ or —C(O)NHR′groups. The groups denoted R′ above may be —H or any —C₁-C₆ alkyl.

An aryl group includes any unsubstituted or substituted phenyl ornapthyl group. Examples of groups that may be substituted onto ay arylgroup include, but are not limited to: halo, —C₁-C₆ alkyl, —O—(C₁-C₆alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R′)2, —NHC(O), R′, or—C(O)NEtR′. The group denoted R′ may be —H or any —C₁-C₆ alkyl.

A C₃-C₇ cycloalkyl group includes any 3-, 4-, 5-, 6-, or 7-memberedsubstituted or unsubstituted non-aromatic carbocyclic ring. Examples ofC₃-C₇ cycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptanyl,1,3-cyclohexadienyl,-1,4-cyclohexadienyl,-1,3-cycloheptadienyl, and-1,3,5-cycloheptatrienyl groups. Examples of groups that may besubstituted onto C₃-C₇ cycloalkyl groups include, but are not limitedto: -halo, —C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —OH, —CN, —COOR′, —OC(O)R′,NHR′, N(R′)₂, —NHC(O)R′ or —C(O)NHR′ groups. The groups denoted R′ aboveinclude an —H or any unsubstituted —C₁-C₆ alkyl, examples of which arelisted above. Halo groups include any halogen. Examples include but arenot limited to —F, —Cl, —Br, or —I.

A heterocycle may be any optionally substituted saturated, unsaturatedor aromatic cyclic moiety wherein said cyclic moiety is interrupted byat least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen(N). Heterocycles may be monocyclic or polycyclic rings. For example,suitable substituents include halogen, halogenated C1-6 alkyl,halogenated C1-6 alkoxy, amino, amidino, amido, azido, cyano, guanidino,hydroxyl, nitro, nitroso, urea, OS(O)₂R; OS(O)₂OR, S(O)₂OR S(O)₀₋₂R,C(O)OR wherein R may be H, C₁-C₆ alkyl, aryl or 3 to 10 memberedheterocycle) OP(O)OR₁OR₂, P(O)OR₁OR₂, SO₂NR₁R₂, NR₁SO₂R₂ C(R₁)NR₂C(Ri)NOR₂, R1 and R2 may be independently H, C₁-C₆ alkyl, aryl or 3 to10 membered heterocycle), NR₁C(O)R₂, NR₁C(O)OR₂, NR₃C(O)NR₂R₁,C(O)NR₁R₂, OC(O)NR₁R₂. For these groups, R₁, R₂ and R₃ are eachindependently selected from H, C₁-C₆ alkyl, aryl or 3 to 10 memberedheterocycle or R₁ and R₂ are taken together with the atoms to which theyare attached to form a 3 to 10 membered heterocycle.

Possible substituents of heterocycle groups include halogen (Br, Cl, Ior F), cyano, nitro, oxo, amino, C₁₋₄ alkyl (e.g., CH₃, C₂H₅, isopropyl)C₁₋₄ alkoxy (e.g., OCH₃, OC₂H₅), halogenated C₁₋₄ alkyl (e.g., CF₃,CHF₂), halogenated C₁₋₄ alkoxy (e.g., OCF₃, OC₂F₅), COOH, COO—C₁₋₄alkyl, CO—C₁₋₄ alkyl, C₁₋₄ alkyl —S— (e.g., CH₃S, C₂H₅S), halogenatedC₁₋₄ alkyl —S— (e.g., CF₃S, C₂F₅S), benzyloxy, and pyrazolyl.

Examples of heterocycles include but are not limited to azepinyl,aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl,dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl,isothiazolyl, imidazolyl, morpholinyl, morpholino, oxetanyl,oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl,pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl,thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl,triazinyl, thiazinyl, thiopyranyl furoisoxazolyl, imidazothiazolyl,thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl,cyclopentapyrazolyl, pyrrolopyrrolyl, thienothienyl,thiadiazolopyrimidinyl, thiazolothiazinyl, thiazolopyrimidinyl,thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl,benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl,pyrazolopyrimidinyl, imidazopyridinyl, benzimidazolyl, indazolyl,benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl,isoindolinyl, furopyrimidinyl, furopyridyl, benzofuranyl,isobenzofuranyl, thienopyrimidinyl, thienapyridyl, benzothienyl,cyclopentaoxazinyl, cyclopentafuranyl, benzoxazinyl, benzothiazinyl,quinazolinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl,pyridopyridazinyl and pyridopyrimidinyl groups.

The disclosed compound and its intermediates may exist in differenttautomeric forms. Tautomers include any structural isomers of differentenergies that have a low energy barrier to interconversion. One exampleis proton tautomers (prototropic tautomers.) In this example, theinterconversions occur via the migration of a proton. Examples ofprototropic tautomers include but are not limited to keto-enol andimine-enamine isomerizations. In another example illustrated graphicallybelow, proton migration between the 1-position and 3-position nitrogenatoms of the benzimidazole ring may occur. As a result, Formulas Ia andIb are tautomeric forms of each other:

The invention further encompasses any other physiochemical orsterochemical form that the disclosed compound may assume. Such formsinclude diastereomers, racemates, isolated enantiomers, hydrated forms,solvated forms, or any other known or yet to be disclosed crystalline,polymorphic crystalline, or amorphous form. Amorphous forms lack adistinguishable crystal lattice and therefore lack an orderlyarrangement of structural units. Many pharmaceutical compounds haveamorphous forms. Methods of generating such chemical forms will be wellknown by one with skill in the art.

In some aspects of the invention the disclosed compound is in the formof a pharmaceutically acceptable salt. Pharmaceutically acceptable saltsinclude any salt derived from an organic or inorganic acid. Examples ofsuch salts include but are not limited to the following: salts ofhydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid andsulphuric acid. Organic acid addition salts include, for example, saltsof acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonicacid, citric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid,1,2-ethanedisulphonic acid, ethanesulphonic acid,ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonicacid, gluconic acid, glutamic acid, N-glycolylarsanilic acid,4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid,1-hydroxy-2-naphthoicacid, 3-hydroxy-2-naphthoic acid,2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuricacid, maleic acid, malic acid, mandelic acid, methanesulphonic acid,methyl sulpuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoicacid, pantothenic acid, phosphanilic acid ((4-aminophenyl) phosphonicacid), picric acid, salicylic acid, stearic acid, succinic acid, tannicacid, tartaric acid, terephthalic acid, p-toluenesulphonic acid,10-undecenoic acid or any other such acid now known or yet to bedisclosed. It will be appreciated by one skilled in the art that suchpharmaceutically acceptable salts may be used in the formulation of apharmacological composition. Such salts may be prepared by reacting thedisclosed compound with a suitable acid in a manner known by thoseskilled in the art.

The invention further encompasses aspects in which a protecting group isadded to the compound. One skilled in the art would recognize thatduring the synthesis of complex molecules, one group on the disclosedcompound may happen to interfere with an intended reaction that includesa second group on the compound. Temporarily masking or protecting thefirst group encourages the desired reaction. Protection involvesintroducing a protecting group to a group to be protected, carrying outthe desired reaction, and removing the protecting group Removal of theprotecting group may be referred to as deprotection. Examples ofcompounds to be protected in some syntheses include hydroxy groups,amine groups, carbonyl groups, carboxyl groups and thiols.

Many protective groups and reagents capable of introducing them intosynthetic processes have been and are continuing to be developed today.A protecting group may result from any chemical synthesis thatselectively attaches a group that is resistant to certain reagents tothe chemical group to be protected without significant effects on anyother chemical groups in the molecule, remains stable throughout thesynthesis, and may be removed through conditions that do not adverselyreact with the protected group, nor any other chemical group in themolecule. Multiple protecting groups may be added throughout a synthesisand one skilled in the art would be able to develop a strategy forspecific addition and removal of the protecting groups to and from thegroups to be protected.

Protecting groups, reagents that add those groups, preparations of thosereagents, protection and deprotection strategies under a variety ofconditions, including complex syntheses with mutually complementaryprotecting groups are all well known in the art. Nonlimiting examples ofall of these may be found in Green et al, Protective Groups in OrganicChemistry 2^(nd) Ed., (Wiley 1991), and Harrison et al, Compendium ofSynthetic Organic Methods, Vols. 1-8 (Wiley, 1971-1996) both of whichhereby incorporated by reference in its entirety.

Racemates, individual enantiomers, or diasteromers of the disclosedcompound may be prepared by specific synthesis or resolution through anymethod now known or yet to be disclosed. For example, the disclosedcompound may be resolved into it enantiomers by the formation ofdiasteromeric pairs through salt formation using an optically activeacid. Enantiomers are fractionally crystallized and the free baseregenerated. In another example, enantiomers may be separated bychromatography. Such chromatography may be any appropriate method nowknown or yet to be disclosed that is appropriate to separate enantiomerssuch as HPLC on a chiral column.

The invention further encompasses pharmaceutical compositions thatinclude the disclosed compound as an ingredient. Such pharmaceuticalcompositions may take any physical form necessary depending on a numberof factors including the desired method of administration and thephysicochemical and stereochemical form taken by the disclosed compoundor pharmaceutically acceptable salts of the compound. Such physicalforms include a solid, liquid, gas, sol, gel, aerosol, or any otherphysical form now known or yet to be disclosed. The concept of apharmaceutical composition including the disclosed compound alsoencompasses the disclosed compound or a pharmaceutically acceptable saltthereof without any other additive. The physical form of the inventionmay affect the route of administration and one skilled in the art wouldknow to choose a route of administration that takes into considerationboth the physical form of the compound and the disorder to be treated.Pharmaceutical compositions that include the disclosed compound may beprepared using methodology well known in the pharmaceutical art. Apharmaceutical composition that includes the disclosed compound mayinclude a second effective compound of a distinct chemical formula fromthe disclosed compound. This second effective compound may have the sameor a similar molecular target as the target or it may act upstream ordownstream of the molecular target of the disclosed compound with regardto one or more biochemical pathways.

Pharmaceutical compositions including the disclosed compound includematerials capable of modifying the physical form of a dosage unit. Inone nonlimiting example, the composition includes a material that formsa coating that holds in the compound. Materials that may be used in sucha coating, include, for example, sugar, shellac, gelatin, or any otherinert coating agent.

Pharmaceutical compositions including the disclosed compound may beprepared as a gas or aerosol. Aerosols encompass a variety of systemsincluding colloids and pressurized packages. Delivery of a compositionin this form may include propulsion of a pharmaceutical compositionincluding the disclosed compound through use of liquefied gas or othercompressed gas or by a suitable pump system. Aerosols may be deliveredin single phase, bi-phasic, or tri-phasic systems.

In some aspects of the invention, the pharmaceutical compositionincluding the disclosed compound is in the form of a solvate. Suchsolvates are produced by the dissolution of the disclosed compound in apharmaceutically acceptable solvent. Pharmaceutically acceptablesolvents include any mixtures of more than one solvent. Such solventsmay include pyridine, chloroform, propan-1-ol, ethyl oleate, ethyllactate, ethylene oxide, water, ethanol, and any other solvent thatdelivers a sufficient quantity of the disclosed compound to treat theaffliction without serious complications arising from the use of thesolvent in patients.

Pharmaceutical compositions that include the disclosed compound may alsoinclude a pharmaceutically acceptable carrier. Carriers include anysubstance that may be administered with the disclosed compound with theintended purpose of facilitating, assisting, or helping theadministration or other delivery of the compound. Carriers include anyliquid, solid, semisolid, gel, aerosol or anything else that may becombined with the disclosed compound to aid in its administration.Examples include diluents, adjuvants, excipients, water, oils (includingpetroleum, animal, vegetable or synthetic oils,) Such carriers includeparticulates such as a tablet or powder, liquids such as an oral syrupor injectable liquid, and inhalable aerosols. Further examples includesaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, and urea. Such carriers may further include binders such asethyl cellulose, carboxymethylcellulose, microcrystalline cellulose, orgelatin; excipients such as starch, lactose or dextrins; disintegratingagents such as alginic acid, sodium alginate, Primogel, and corn starch;lubricants such as magnesium stearate or Sterotex; glidants such ascolloidal silicon dioxide; sweetening agents such as sucrose orsaccharin, a flavoring agent such as peppermint, methyl salicylate ororange flavoring, or coloring agents. Further examples of carriersinclude polyethylene glycol, cyclodextrin, oils, or any other similarliquid carrier that may be formulated into a capsule. Still furtherexamples of carriers include sterile diluents such as water forinjection, saline solution, physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordigylcerides, polyethylene glycols, glycerin, cyclodextrin, propyleneglycol or other solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose, thickening agents,lubricating agents, and coloring agents.

The pharmaceutical composition including the disclosed compound may takeany of a number of formulations depending on the physicochemical form ofthe composition and the type of administration. Such forms includesolutions, suspensions, emulsions, tablets, pills, pellets, capsules,capsules including liquids, powders, sustained-release formulations,directed release formulations, lyophylates, suppositories, emulsions,aerosols, sprays, granules, powders, syrups, elixirs, or any otherformulation now known or yet to be disclosed. Additional examples ofsuitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences” by E. W. Martin, hereby incorporated byreference in its entirety.

Methods of administration include, but are not limited to, oraladministration and parenteral administration. Parenteral administrationincludes, but is not limited to intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, epidural,sublingual, intramsal, intracerebral, iratraventricular, intrathecal,intravaginal, transdermal, rectal, by inhalation, or topically to theears, nose, eyes, or skin. Other methods of administration include butare not limited to infusion techniques including infusion or bolusinjection, by absorption through epithelial or mucocutaneous liningssuch as oral mucosa, rectal and intestinal mucosa. Compositions forparenteral administration may be enclosed in ampoule, a disposablesyringe or a multiple-dose vial made of glass, plastic or othermaterial.

Administration may be systemic or local. Local administration isadministration of the disclosed compound to the area in need oftreatment. Examples include local infusion during surgery; topicalapplication, by local injection; by a catheter; by a suppository; or byan implant. Administration may be by direct injection at the site (orformer site) of a cancer, tumor, or precancerous tissue or into thecentral nervous system by any suitable route, including intraventricularand intrathecal injection. Intraventricular injection may be facilitatedby an intraventricular catheter, for example, attached to a reservoir,such as an Ommaya reservoir. Pulmonary administration may be achieved byany of a number of methods known in the art. Examples include use of aninhaler or nebulizer, formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Thedisclosed compound may be delivered in the context of a vesicle such asa liposome or any other natural or synthetic vesicle.

A pharmaceutical composition formulated so as to be administered byinjection may be prepared by dissolving the disclosed compound withwater so as to form a solution. In addition, a surfactant may be addedto facilitate the formation of a homogeneous solution or suspension.Surfactants include any complex capable of non-covalent interaction withthe disclosed compound so as to facilitate dissolution or homogeneoussuspension of the compound.

Pharmaceutical compositions including the disclosed compound may beprepared in a form that facilitates topical or transdermaladministration. Such preparations may be in the form of a solution,emulsion, ointment, gel base, transdermal patch or iontophoresis device.Examples of bases used in such compositions include opetrolatum,lanolin, polyethylene glycols, beeswax, mineral oil, diluents such aswater and alcohol, and emulsifiers and stabilizers, thickening agents,or any other suitable base now known or yet to be disclosed.

Cancer cells include any cells derived from a tumor, neoplasm, cancer,precancer, cell line, or any other source of cells that are ultimatelycapable of potentially unlimited expansion and growth. Cancer cells maybe derived from naturally occurring sources or may be artificiallycreated. Cancer cells may also be capable of invasion into other tissuesand metastasis when placed into an animal host. Cancer cells furtherencompass any malignant cells that have invaded other tissues and/ormetastasized. One or more cancer cells in the context of an organism mayalso be called a cancer, tumor, neoplasm, growth, malignancy, or anyother term used in the art to describe cells in a cancerous state.

Expansion of a cancer cell includes any process that results in anincrease in the number of individual cells derived from a cancer cell.Expansion of a cancer cell may result from mitotic division,proliferation, or any other form of expansion of a cancer cell, whetherin vitro or in vivo. Expansion of a cancer cell further encompassesinvasion and metastasis. A cancer cell may be in physical proximity tocancer cells from the same clone or from different clones that may ormay not be genetically identical to it. Such aggregations may take theform of a colony, tumor or metastasis, any of which may occur in vivo orin vitro. Slowing the expansion of the cancer cell may be brought abouteither by inhibiting cellular processes that promote expansion or bybringing about cellular processes that inhibit expansion. Processes thatinhibit expansion include processes that slow mitotic division andprocesses that promote cell senescence or cell death. Examples ofspecific processes that inhibit expansion include caspase dependent andindependent pathways, autophagy, necrosis, apoptosis, and mitochondrialdependent and independent processes and further include any suchprocesses yet to be disclosed. Slowing the expansion of a cancer cellmay also involve inhibition of processes that promote vascularization,migration or metastasis or in the promotion of processes that inhibitvascularization, migration or metastasis. Slowing the expansion of acancer cell may further involve the promotion of processes that make acancer cell more visible to the immune system or any other process bywhich progression of cancer may be retarded, halted, or reversed.

Addition of a pharmaceutical composition to cancer cells includes allactions by which an effect of the pharmaceutical composition on thecancer cell is realized. The type of addition chosen will depend uponwhether the cancer cells are in vivo, ex vivo, or in vitro, the physicalor chemical properties of the pharmaceutical composition, and the effectthe composition is to have on the cancer cell. Nonlimiting examples ofaddition include addition of a solution including the pharmaceuticalcomposition to tissue culture media in which in vitro cancer cells aregrowing; any method by which a pharmaceutical composition may beadministered to an animal including intravenous, per os, parenteral, orany other of the methods of administration; or the activation orinhibition of cells that in turn have effects on the cancer cells suchas immune cells (e.g. macophages and CD8+ T cells) or endothelial cellsthat may differentiate into blood vessel structures in the process ofangiogenesis or vasculogenesis.

Determination of an effective amount of the disclosed compound is withinthe capability of those skilled in the art, especially in light of thedetailed disclosure provided herein. The effective amount of apharmaceutical composition used to effect a particular purpose as wellas its toxicity, excretion, and overall tolerance may be determined incell cultures or experimental animals by pharmaceutical andtoxicological procedures either known now by those skilled in the art orby any similar method yet to be disclosed. One example is thedetermination of the IC₅₀ (half maximal inhibitory concentration) of thepharmaceutical composition in vitro in cell lines or using targetmolecules. Another example is the determination of the LD₅₀ (lethal dosecausing death in 50% of the tested animals) of the pharmaceuticalcomposition in experimental animals. The exact techniques used indetermining an effective amount will depend on factors such as the typeand physical/chemical properties of the pharmaceutical composition, theproperty being tested, and whether the test is to be performed in vitroor in vivo. The determination of an effective amount of a pharmaceuticalcomposition will be well known to one of skill in the art who will usedata obtained from any tests in making that determination. Determinationof an effective amount of disclosed compound for addition to a cancercell also includes the determination of an effective therapeutic amount,including the formulation of an effective dose range for use in vivo,including in humans.

Treatment is contemplated in living entities including but not limitedto mammals (particularly humans) as well as other mammals of economic orsocial importance, including those of an endangered status. Furtherexamples include livestock or other animals generally bred for humanconsumption and domesticated companion animals.

The effective amount of the disclosed compound that results in a slowingof expansion of the cancer cells would be a concentration at or near thetarget tissue that is effective in slowing cellular expansion inneoplastic cells, with a lesser effect (up to and including no effect)on non-neoplastic cells, including non-neoplastic cells previously orconcurrently exposed to radiation or chemotherapeutic chemical agents.Concentrations that produce these effects can be determined using, forexample, apoptosis markers such as the apoptotic index and/or caspaseactivities either in vitro or in vivo.

Treatment of a condition is the practice of any method, process, orprocedure with the intent of halting, inhibiting, slowing or reversingthe progression of a disease, disorder or condition, substantiallyameliorating clinical symptoms of a disease disorder or condition, orsubstantially preventing the appearance of clinical symptoms of adisease, disorder or condition, up to and including returning thediseased entity to its condition prior to the development of thedisease.

The addition of a therapeutically effective amount of the disclosedcompound encompasses any method of dosing of a compound. Dosing of thedisclosed compound may include single or multiple administrations of anyof a number of pharmaceutical compositions that include the disclosedcompound as an active ingredient. Examples include a singleadministration of a slow release composition, a course of treatmentinvolving several treatments on a regular or irregular basis, multipleadministrations for a period of time until a diminution of the diseasestate is achieved, preventative treatments applied prior to theinstigation of symptoms, or any other dosing regimen known in the art oryet to be disclosed that one skilled in the art would recognize as apotentially effective regimen. A final dosing regimen including theregularity of and mode of administration will be dependent on any of anumber of factors including but not limited to the subject beingtreated; the severity of the affliction; the manner of administration,the stage of disease development, the presence of one or more otherconditions such as pregnancy, infancy, or the presence of one or moreadditional diseases; or any other factor now known or yet to bedisclosed that affects the choice of the mode of administration, thedose to be administered and the time period over which the dose isadministered.

Pharmaceutical compositions that include the disclosed compound may beadministered prior to, concurrently with, or after administration of asecond pharmaceutical composition that may or may not include thecompound. If the compositions are administered concurrently, they areadministered within one minute of each other. If not administeredconcurrently, the second pharmaceutical composition may be administereda period of one or more minutes, hours, days, weeks, or months before orafter the pharmaceutical composition that includes the compoundAlternatively, a combination of pharmaceutical compositions may becyclically administered. Cycling therapy involves the administration ofone or more pharmaceutical compositions for a period of time, followedby the administration of one or more different pharmaceuticalcompositions for a period of time and repeating this sequentialadministration, in order to reduce the development of resistance to oneor more of the compositions, to avoid or reduce the side effects of oneor more of the compositions, and/or to improve the efficacy of thetreatment.

The invention further encompasses kits that facilitate theadministration of the disclosed compound to a diseased entity. Anexample of such a kit includes one or more unit dosages of the compound.The unit dosage would be enclosed in a preferably sterile container andwould be comprised of the disclosed compound and a pharmaceuticallyacceptable carrier. In another aspect, the unit dosage would compriseone or more lyophilates of the compound. In this aspect of theinvention, the kit may include another preferably sterile containerenclosing a solution capable of dissolving the lyophilate. However, sucha solution need not be included in the kit and may be obtainedseparately from the lyophilate. In another aspect, the kit may includeone or more devices used in administrating the unit dosages or apharmaceutical composition to be used in combination with the compound.Examples of such devices include, but are not limited to, a syringe, adrip bag, a patch or an enema. In some aspects of the invention, thedevice comprises the container that encloses the unit dosage.

Pharmaceutical compositions including the disclosed compound may be usedin methods of treating cancer. Such methods involve the administrationof a therapeutic amount of a pharmaceutical composition that includesthe disclosed compound and/or a pharmaceutically acceptable salt thereofto a mammal, preferably a mammal in which a cancer has been diagnosed.

A therapeutic amount further includes an amount of that results in theprevention of progression of the cancer to a neoplastic, malignant ormetastatic state. Such preventative use is indicated in conditions knownor suspected of preceding progression to neoplasia or cancer, inparticular, where non-neoplastic cell expansion consisting ofhyperplasia, metaplasia, or dysplasia has occurred (for review of suchabnormal expansion conditions, see Robbins and Angell, 1976, BasicPathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-79).Hyperplasia is a form of controlled cell proliferation involving anincrease in cell number in a tissue or organ, without significantalteration in structure or activity. For example, endometrialhyperplasia often precedes endometrial cancer and precancerous colonpolyps often transform into cancerous lesions. Metaplasia is a form ofcontrolled cell expansion in which one type of adult or fullydifferentiated cell substitutes for another type of adult cell.Metaplasia can occur in epithelial or connective tissue cells. A typicalmetaplasia involves a somewhat disorderly metaplastic epithelium.Dysplasia is frequently a forerunner of cancer, and is found mainly inthe epithelia; it is the most disorderly form of non-neoplastic cellexpansion, involving a loss in individual cell uniformity and in thearchitectural orientation of cells. Dysplastic cells often haveabnormally large, deeply stained nuclei, and exhibit pleomorphism.Dysplasia characteristically occurs where there exists chronicirritation or inflammation, and is often found in the cervix,respiratory passages, oral cavity, and gall bladder.

Alternatively or in addition to the presence of abnormal cell expansioncharacterized as hyperplasia, metaplasia, or dysplasia, the presence ofone or more characteristics of a transformed phenotype or of a malignantphenotype, displayed in vivo or displayed in vitro by a cell samplederived from a patient can indicate the desirability ofprophylactic/therapeutic administration of the pharmaceuticalcomposition that includes the compound. Such characteristics of atransformed phenotype include morphology changes, looser substratumattachment, loss of contact inhibition, loss of anchorage dependence,protease release, increased sugar transport, decreased serumrequirement, expression of fetal antigens, disappearance of the 250,000dalton cell surface protein, etc. (see also id., at pp. 84-90 forcharacteristics associated with a transformed or malignant phenotype).Further examples include leukoplakia, in which a benign-appearinghyperplastic or dysplastic lesion of the epithelium, or Bowen's disease,a carcinoma in situ, are pre-neoplastic lesions indicative of thedesirability of prophylactic intervention. In another example,fibrocystic disease including cystic hyperplasia, mammary dysplasia,adenosis, or benign epithelial hyperplasia is indicates desirability ofprophylactic intervention.

In some aspects of the invention, use of the disclosed compound may bedetermined by one or more physical factors such as tumor size and gradeor one or more molecular markers and/or expression signatures thatindicate prognosis and the likely response to treatment with thecompound. For example, determination of estrogen (FR) and progesterone(PR) steroid hormone receptor status has become a routine procedure inassessment of breast cancer patients. See, for example, Fitzgibbons etal, Arch. Pathol. Lab. Med. 124:966-78, 2000. Tumors that are hormonereceptor positive are more likely to respond to hormone therapy and alsotypically grow less aggressively thereby resulting in a better prognosisfor patients with ER+/PR+ tumors. In a further example, overexpressionof human epidermal growth factor receptor 2 (HER-2/neu), a transmembranetyrosine kinase receptor protein, has been correlated with poor breastcancer prognosis (see, e.g., Ross et al, The Oncologist 8:307-25, 2003),and Her-2 expression levels in breast tumors are used to predictresponse to the anti-Her-2 monoclonal antibody therapeutic trastuzumab(Herceptin®, Genentech, South San Francisco, Calif.).

In another aspect of the invention, the diseased entity exhibits one ormore predisposing factors for malignancy that may be treated byadministration of a pharmaceutical composition including the compound.Such predisposing factors include but are not limited to chromosomaltranslocations associated with a malignancy such as the Philadelphiachromosome for chronic myelogenous leukemia and t (14; 18) forfollicular lymphoma; an incidence of polyposis or Gardner's syndromethat are indicative of colon cancer; benign monoclonal gammopathy whichis indicative of multiple myeloma, kinship with persons who have had orcurrently have a cancer or precancerous disease, exposure tocarcinogens, or any other predisposing factor that indicates inincreased incidence of cancer now known or yet to be disclosed.

The invention further encompasses methods of treating cancer thatcomprise combination therapies that comprise the administration of apharmaceutical composition including the disclosed compound and anothertreatment modality. Such treatment modalities include but are notlimited to, radiotherapy, chemotherapy, surgery, immunotherapy, cancervaccines, radioimmunotherapy, treatment with pharmaceutical compositionsother than those which include the disclosed compound, or any othermethod that effectively treats cancer in combination with the disclosedcompound now known or yet to be disclosed. Combination therapies may actsynergistically. That is, the combination of the two therapies is moreeffective than either therapy administered alone. This results in asituation in which lower dosages of both treatment modality may be usedeffectively. This in turn reduces the toxicity and side effects, if any,associated with the administration either modality without a reductionin efficacy.

In another aspect of the invention, the pharmaceutical compositionincluding the disclosed compound is administered in combination with atherapeutically effective amount of radiotherapy. The radiotherapy maybe administered concurrently with, prior to, or following theadministration of the pharmaceutical composition including the compound.The radiotherapy may act additively or synergistically with thepharmaceutical composition including the compound. This particularaspect of the invention would be most effective in cancers known to beresponsive to radiotherapy. Cancers known to be responsive toradiotherapy include, but are not limited to, Non-Hodgkin's lymphoma,Hodgkin's disease, Ewing's sarcoma, testicular cancer, prostate cancer,ovarian cancer, bladder cancer, larynx cancer, cervical cancer,nasopharynx cancer, breast cancer, colon cancer, pancreatic cancer, headand neck cancer, esophogeal cancer, rectal cancer, small-cell lungcancer, non-small cell lung cancer, brain tumors, other CNS neoplasms,or any other such tumor now known or yet to be disclosed.

Examples of pharmaceutical compositions that may be used in combinationwith the disclosed compound may include nucleic acid bindingcompositions such as cis-diamminedichloro platinum (II) (cisplatin),doxorubicin, 5-fluorouracil, taxol, and topoisomerase inhibitors such asetoposide, teniposide, irinotecan and topotecan. Still otherpharmaceutical compositions include antiemetic compositions such asmetoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,thioproperazine and tropisetron.

Still other examples of pharmaceutical compositions that may be used incombination with the pharmaceutical composition including the disclosedcompound are hematopoietic colony stimulating factors. Examples ofhematopoietic colony stimulating factors include, but are not limitedto, filgrastim, sargramostim, molgramostim and epoietin alfa.Alternatively, the pharmaceutical composition including the disclosedcompound may be used in combination with an anxiolytic agent. Examplesof anxiolytic agents include, but are not limited to, buspirone, andbenzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate,clonazepam, chlordiazepoxide and alprazolam.

Pharmaceutical compositions that may be used in combination withpharmaceutical compositions that include the disclosed compound mayinclude analgesic agents. Such agents may be opioid or non-opioidanalgesic. Non-limiting examples of opioid analgesics inlcude morphine,heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon,apomorphine, normorphine, etorphine, buprenorphine, meperidine,lopermide, anileridine, ethoheptazine, piminidine, betaprodine,diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil,levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine,methadone, isomethadone and propoxyphene. Suitable non-opioid analgesicagents include, but are not limited to, aspirin, celecoxib, rofecoxib,diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid,nabumetone, naproxen, piroxicam, sulindac or any other analgesic nowknown or yet to be disclosed.

In other aspects of the invention, pharmaceutical compositions includingthe disclosed compound may be used in combination with a method thatinvolves treatment of cancer ex vivo. One example of such a treatment isan autologous stem cell transplant. In this method, a diseased entity'sautologous hematopoietic stem cells are harvested and purged of allcancer cells. A therapeutic amount of a pharmaceutical compositionincluding the disclosed compoundmay then be administered to the patientprior to restoring the entity's bone marrow by addition of either thepatient's own or donor stem cells.

Cancers that may be treated by pharmaceutical compositions including thedisclosed compound either alone or in combination with another treatmentmodality include solid tumors such as fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer,pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostatecancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer,throat cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms'tumor, cervical cancer, uterine cancer, testicularcancer, small cell lung carcinoma, bladder carcinoma, lung cancer,epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, and retinoblastoma.

Additional cancers that may be treated by pharmaceutical compositionsincluding the disclosed compound include blood borne cancers such asacute lymphoblastic leukemia (“ALL,”), acute lymphoblastic B-cellleukemia, acute lymphoblastic T-cell leukemia, acute myeloblasticleukemia (“AML”), acute promyelocytic leukemia (“APL”), acutemonoblastic leukemia, acute erythroleukemic leukemia, acutemegakaryoblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocyctic leukemia, acute undifferentiated leukemia, chronicmyelocytic leukemia (“CML”), chronic lymphocytic leukemia (“CLL”), hairycell leukemia, multiple myeloma, lymphoblastic leukemia, myelogenousleukemia, lymphocytic leukemia, myelocytic leukemia, Hodgkin's disease,non-Hodgkin's Lymphoma, Waldenstrom's macroglobulinemia, Heavy chaindisease, and Polycythemia vera.

Examples that represent different aspects of the invention follow. Suchexamples should not be construed as limiting the scope of thedisclosure. Alternative mechanistic pathways and analogous structureswithin the scope of the invention would be apparent to those skilled inthe art.

EXAMPLES

Elements and acts in the example are intended to illustrate theinvention for the sake of simplicity and have not necessarily beenrendered according to any particular sequence or embodiment. The exampleis also intended to establish possession of the invention by theInventors.

The synthesis of the target compounds starts with an amide formationreaction between carboxylic acid of formula 1 and aniline of formula 2or amino thiazole of formula 3 mediated byN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) and diisopropylethylamine (DIEA) inN,N-dimethylformaldehyde (DMF). The coupling product of formula 4 or 5is treated with hydroxylamine and sodium hydroxide in tetrahydrofuranand methyl alcohol solution yields the corresponding hydroxamic acid offormula 6 or 7.

Example 1N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide.(Compound ID #8)

Step 1. To a solution of 2-(4-methoxyphenyl)butanoic acid (135 mg, 0.70mmol) and ethyl 2-aminothiazole-5-carboxylate (100 mg, 0.58 mmol) in DMFwere added DIEA (112 mg, 0.87 mmol) and HATU (264 mg, 0.70 mmol). Thereaction was stirred at room temperature for 4 hrs and partitionedbetween ethyl acetate and water. The organic layer was dried andconcentrated. The residue was purified by biotage column chromatographyto afford ethyl 2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxylate(163 mg).

Step 2. To a solution of methyl2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxylate (112 mg, 0.322mmol) in a mixture of tetrahydrofuran/methanol (4:1) was added 2.8 mL ofhydroxylamine (50% in water) followed by sodium hydroxide solution (1 N,1.0 mL). The mixture was stirred at room temperature overnight andconcentrated. The residue was acidified with 1 N HCl and purified by C18biotage column chromatography to afford compound #8 (71 mg). MS(calculated for M+1: 349. found 349)

Example 2N-hydroxy-2-(3-methyl-2-phenylbutanamido)thiazole-5-carboxamide.(Compound ID #1)

The compound was prepared using 3-methyl-2-phenylbutanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 320. found 320)

Example 3 N-hydroxy-2-(2-phenylbutanamido)thiazole-5-carboxamide.(Compound ID #2)

The compound was prepared using 2-phenylbutanoic acid and otherwise byfollowing the synthesis method of Example 1. MS (calculated for M+1:306. found 306)

Example 4N-hydroxy-2-(1-phenylcyclopropanecarboxamido)thiazole-5-carboxamide.(Compound ID #3)

The compound was prepared using 1-phenylcyclopropanecarboxylic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 304. found 304)

Example 5N-hydroxy-2-(2-methyl-2-phenylpropanamido)thiazole-5-carboxamide.(Compound ID #4)

The compound was prepared using 2-methyl-2-phenylpropanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 306. found 306)

Example 6 N-hydroxy-2-(2-phenylacetamido)thiazole-5-carboxamide.(Compound ID #5)

The compound was prepared using 2-phenylacetic acid and otherwise byfollowing the synthesis method of Example 1. MS (calculated for M+1:278. found 278)

Example 7 N-hydroxy-2-(3-phenylpropanamido)thiazole-5-carboxamide.(Compound ID #6)

The compound was prepared using 3-phenylpropanoic acid and otherwise byfollowing the synthesis method of Example 1. MS (calculated for M+1:292. found 292)

Example 8N-hydroxy-2-(2-methoxy-2-phenylacetamido)thiazole-5-carboxamide.(Compound ID #7)

The compound was prepared using 2-methoxy-2-phenylacetic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 308. found 308)

Example 9 N-hydroxy-2-(2-phenylpropanamido)thiazole-5-carboxamide.(Compound ID #9)

The compound was prepared using 2-phenylpropanoic acid and otherwise byfollowing the synthesis method of Example 1. MS (calculated for M+1:292. found 292)

Example 102-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #10)

The compound was prepared using 2-(4-chlorophenyl)-3-methylbutanoic acidand otherwise by following the synthesis method of Example 1. MS(calculated for M+1: 354. found 354)

Example 112-(2,2-dimethyl-3-phenylpropanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #11)

The compound was prepared using 2,2-dimethyl-3-phenylpropanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 320. found 320)

Example 12 4-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxybenzamide.(Compound ID #12)

The compound was prepared using 2-(4-chlorophenyl)-3-methylbutanoic acidand ethyl 4-aminobenzoate and otherwise by following the synthesismethod of Example 1. MS (calculated for M+1: 347. found 347)

Example 132-(2-(4-bromophenyl)butanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #13)

The compound was prepared using 2-(4-bromophenyl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 385. found 385)

Example 14N-hydroxy-2-(4-methoxy-2-phenylbutanamido)thiazole-5-carboxamide.(Compound ID #14)

The compound was prepared using 4-methoxy-2-phenylbutanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 336. found 336)

Example 15 N-hydroxy-4-(2-(4-methoxyphenyl)butanamido)benzamide.(Compound ID #15)

The compound was prepared using 2-(4-methoxyphenyl)butanoic acid andethyl 4-aminobenzoate and otherwise by following the synthesis method ofExample 1. MS (calculated for M+1: 329. found 329)

Example 16N-hydroxy-2-(3-methoxy-2-phenylpropanamido)thiazole-5-carboxamide.(Compound ID #16)

The compound was prepared using 3-methoxy-2-phenylpropanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 322. found 322)

Example 172-(2-(biphenyl-4-yl)butanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #17)

The compound was prepared using 2-(biphenyl-4-yl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 382. found 382)

Example 18N-hydroxy-2-(2-(4-(pyrimidin-5-yl)phenyl)butanamido)thiazole-5-carboxamide.(Compound ID #18)

The compound was prepared using 2-(4-(pyrimidin-5-yl)phenyl)butanoicacid and otherwise by following the synthesis method of Example 1. MS(calculated for M+1: 384. found 384)

Example 192-(2-(4-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #19)

The compound was prepared using 2-(4-fluorophenyl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 324. found 324)

Example 202-(2-(3-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #20)

The compound was prepared using 2-(3-fluorophenyl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 324. found 324)

Example 21N-hydroxy-2-(2-(4-hydroxyphenyl)-3-methylbutanamido)thiazole-5-carboxamide.(Compound ID #21)

The compound was prepared using 2-(4-hydroxyphenyl)-3-methylbutanoicacid and otherwise by following the synthesis method of Example 1. MS(calculated for M+1: 336. found 336)

Example 22N-hydroxy-2-(2-(3-methoxyphenyl)butanamido)thiazole-5-carboxamide.(Compound ID #22)

The compound was prepared using 2-(3-methoxyphenyl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 336. found 336)

Example 23N-hydroxy-2-(2-(2-methoxyphenyl)butanamido)thiazole-5-carboxamide.(Compound ID #23)

The compound was prepared using 2-(2-methoxyphenyl)butanoic acid andotherwise by following the synthesis method of Example 1. MS (calculatedfor M+1: 336. found 336)

Example 242-(2-(biphenyl-4-yl)-4-methoxybutanamido)-N-hydroxythiazole-5-carboxamide.(Compound ID #24)

The compound was prepared using 2-(biphenyl-4-yl)-4-methoxybutanoic acidand otherwise by following the synthesis method of Example 1. MS(calculated for M+1: 412. found 412)

Example 25 4-(2-(4-bromophenyl)butanamido)-N-hydroxybenzamide. (CompoundID #25)

The compound was prepared using 2-(4-bromophenyl)butanoic acid and ethyl4-aminobenzoate and otherwise by following the synthesis method ofExample 1. MS (calculated for M+1: 378. found 378)

Example 26 4-(2-(biphenyl-4-yl)butanamido)-N-hydroxybenzamide. (CompoundID #26)

The compound was prepared using 2-(biphenyl-4-yl)butanoic acid and ethyl4-aminobenzoate and otherwise by following the synthesis method ofExample 1. MS (calculated for M+1: 375. found 375)

Example 27 N-hydroxy-4-(4-methoxy-2-phenylbutanamido)benzamide.(Compound ID #27)

The compound was prepared using 3-methoxy-2-phenylpropanoic acid andethyl 4-aminobenzoate and otherwise by following the synthesis method ofExample 1. MS (calculated for M+1: 315. found 315)

Cell viability in the presence of varying concentrations of the abovelisted compounds at different time points was used to assesscytotoxicity and the effect of the compounds on cell proliferation. IC₅₀(or percent activity) data for the disclosed compounds in the SKOV3 andA2780 cell lines are summarized in Table 1. The SKOV3 cell line wasoriginally isolated in 1973 from the ascitic fluid of a patient with anovarian cancer. SKOV3 is a hypodiploid human cell line. SKOV3 cells areresistant to tumor necrosis factor and to several cytotoxic drugsincluding diphtheria toxin, cis-platinum and adriamycin. The A2780 cellline is a human ovarian adenocarcinoma cell line originally derived froma biopsy from an untreated patient. The A2780/CP cell line is a linederived from the A2780 cell line selected for resistance tocis-platinum.

Cell Viability Assay—

Cell viability was measured by the CellTiter-Blue® cell viability assayPromega (Madison, Wis.). This procedure measures the conversion of theindicator dye (resazurin) to resorufin, an indicator of cell viability.Following treatment, growth media was removed and cells were incubatedwith 20 μl of CellTiter-Blue® Reagent and growth media for 1-4 hours at37° C. Fluorescence values were measured at 535/590 nm using aBeckman-Coulter DTX-880 microplate reader.

Experimental Design

Single Agent Studies—

Cells were grown to 70% confluency, trypsinized, counted, and seeded in96 well flat-bottom plates at a final concentration of 2.5×10³-5×10³cells/well (Day 0). Cells were allowed to incubate in growth media for24 hours to allow for maximum adhesion. Treatment with the test agentsor standard agents began on Day 1 and continued for 72 hours. At the 72hour timepoint, treatment containing media was removed. Viable cellnumbers are quantified by the CellTiter-Blue® cell viability assay asdescribed above. Experiments were repeated at least twice with the sameconcentrations to determine growth inhibitory activity. Results fromthese studies were used to calculate an IC₅₀ value (concentration ofdrug that inhibits cell growth by 50 percent of control) for eachcompound.

Data Collection—

For single agent and combination studies, data from each experiment wascollected and expressed as % Cell Expansion using the followingcalculation:

% Cell Expansion=(f _(test) /f _(vehicle))×100

Where f_(test) is the fluorescence of the tested sample, and f_(vehicle)is the fluorescence of the vehicle in which the drug is dissolved. Doseresponse graphs and IC₅₀ values were generated using Prism 4 software(GraphPad) using the following equation:

$Y = \frac{\left( {{Top}\text{-}{Bottom}} \right)}{\left( {1 + 10^{({{({{{logIC}\; 50} - X})} - {HillSlope}})}} \right)}$

Where X is the logarithm of concentration and Y is the response. Ystarts at the Bottom and goes to Top with a sigmoid shape.

TABLE 1 IC₅₀s of indicated cell lines with aspects of the compound shownin the examples. Compound IC50 SKOV3 IC50 A2780 IC50 A2780/CP ID (nM)(nM) (nM) 1 40 ND ND 2 46 0.5 4 3 4100 1200 7500 4 1300 900 7500 5 2100300 1600 6 500 300 3200 7 70 40 20 8 <0.1 <0.1 <0.1 9 30 30 4.8 10 4 1.76.2 11 7500 3800 3800 12 40 30 3 13 2.5 0.5 0.08 14 80 2.4 8.7 15 200.04 0.3 17 0.2 <0.1 0.9 18 100 440 140 19 8.9 <0.1 3 20 4.3 2.4 100 2120 60 40 22 30 600 300 23 2300 100 500 24 30 20 17 25 100 1.1 20 26 1.10.3 1.7 27 900 16 70

1. A compound of formula

wherein X is selected from the group consisting of H, halo, —C₁-C₆alkyl, aryl, —C₃-C₇ cycloalkyl, and -3- to 10-membered heterocycle;wherein Y₁ is selected from the group consisting of H, —C₁-C₆ alkyl, and—C₃-C₇ cycloalkyl; wherein Y₂ is selected from the group consisting ofH, —C₁-C₆ alkyl, and —C₃-C₇ cycloalkyl; wherein Z is selected from thegroup consisting of methyl, —NH2, —NHOH, and phenylene diamine group ofstructure

and all pharmaceutically acceptable salts, solvates, and chemicallyprotected forms thereof.
 2. The compound of claim 1 wherein the compoundis selected from the group consisting of:N-hydroxy-2-(3-methyl-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(1-phenylcyclopropanecarboxamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methyl-2-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(3-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methoxy-2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylpropanamido)thiazole-5-carboxamide;2-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxythiazole-5-carboxamide;2-(2,2-dimethyl-3-phenylpropanamido)-N-hydroxythiazole-5-carboxamide;2-(2-(4-bromophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(4-methoxy-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(3-methoxy-2-phenylpropanamido)thiazole-5-carboxamide;2-(2-(biphenyl-4-yl)butanamido)-N hydroxythiazole-5-carboxamide;N-hydroxy-2-(2-(4-(pyrimidin-5-yl)phenyl)butanamido)thiazole-5-carboxamide;2-(2-(4-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;2-(2-(3-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(2-(4-hydroxyphenyl)-3-methylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(3-methoxyphenyl)butanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(2-methoxyphenyl)butanamido)thiazole-5-carboxamide;2-(2-(biphenyl-4-yl)-4-methoxybutanamido)-N-hydroxythiazole-5-carboxamide;4-(2-(4-bromophenyl)butanamido)-N-hydroxybenzamide;4-(2-(biphenyl-4-yl)butanamido)-N-hydroxybenzamide; andN-hydroxy-4-(4-methoxy-2-phenylbutanamido)benzamide.
 3. A method ofslowing the expansion of a cancer cell comprising adding an effectiveamount of a pharmaceutical composition comprising the compound of claim1 to the cancer cell.
 4. The method of claim 3 wherein thepharmaceutical composition further comprises a pharmaceuticallyacceptable carrier.
 5. The method of claim 3 wherein the compound isselected from the group consisting of:-hydroxy-2-(3-methyl-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(1-phenylcyclopropanecarboxamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methyl-2-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(3-phenylpropanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-methoxy-2-phenylacetamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-phenylpropanamido)thiazole-5-carboxamide;2-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxythiazole-5-carboxamide;2-(2,2-dimethyl-3-phenylpropanamido)-N-hydroxythiazole-5-carboxamide;2-(2-(4-bromophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(4-methoxy-2-phenylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(3-methoxy-2-phenylpropanamido)thiazole-5-carboxamide;2-(2-(biphenyl-4-yl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(2-(4-(pyrimidin-5yl)phenyl)butanamido)thiazole-5-carboxamide;2-(2-(4-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;2-(2-(3-fluorophenyl)butanamido)-N-hydroxythiazole-5-carboxamide;N-hydroxy-2-(2-(4-hydroxyphenyl)-3-methylbutanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(3-methoxyphenyl)butanamido)thiazole-5-carboxamide;N-hydroxy-2-(2-(2-methoxyphenyl)butanamido)thiazole-5-carboxamide;2-(2-(biphenyl-4-yl)-4methoxybutanamido)-N-hydroxythiazole-5-carboxamide;4-(2-(4-bromophenyl)butanamido)-N-hydroxybenzamide;4-(2-(biphenyl-4-yl)butanamido)-N-hydroxybenzamide; andN-hydroxy-4-(4-methoxy-2-phenylbutanamido)benzamide.
 6. The method ofclaim 3 wherein the cancer cell is selected from the group consistingof: an ovarian cancer cell; a pancreatic cancer cell; a breast cancercell; a non-small cell lung cancer cell; an adrenocortical carcinomacell; a lung adenocarcinoma cell; a leukemia cell, and a prostate cancercell. 7-12. (canceled)
 13. The method of claim 3 wherein the cancer cellis resistant to a pharmaceutical composition comprising platinum. 14.The method of claim 3 wherein the slowing of expansion comprises killingthe cancer cell.
 15. A compound of formula

wherein X is selected from the group consisting of H, halo, —C₁-C₆alkyl, aryl, —C₃-C₇ cycloalkyl, and -3- to 10-membered heterocycle;wherein Y1 is selected from the group consisting of H, —C₁-C₆ alkyl, and—C₃-C₇ cycloalkyl; wherein Y2 is selected from the group consisting ofH, —C₁-C₆ alkyl, and —C₃-C₇ cycloalkyl; wherein Z is selected from thegroup consisting of methyl, —NH2, —NHOH, and phenylene diamine group ofstructure

and all pharmaceutically acceptable salts, solvates, and chemicallyprotected forms thereof.
 17. The compound of claim 15 wherein thecompound is selected from the group consisting of4-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxybenzamide andN-hydroxy-4-(2-(4-methoxyphenyl)butanamido)benzamide.
 18. A method ofslowing the expansion of a cancer cell comprising: adding apharmaceutical composition comprising the compound of claim 15 to acancer cell.
 19. The method of claim 18 wherein the compound is selectedfrom the group consisting of4-(2-(4-chlorophenyl)-3-methylbutanamido)-N-hydroxybenzamide andN-hydroxy-4-(2-(4-methoxyphenyl)butanamido)benzamide.
 20. The method ofclaim 18 wherein the pharmaceutical composition further comprises apharmaceutically acceptable carrier.
 21. The method of claim 18 whereinthe cancer cell is selected from the group consisting of: an ovariancancer cell; a pancreatic cancer cell; a breast cancer cell; a non-smallcell lung cancer cell; an adrenocortical carcinoma cell; a lungadenocarcinoma cell; a leukemia cell; and a prostate cancer cell. 22-27.(canceled)
 28. The method of claim 18 wherein the cancer cell isresistant to a pharmaceutical composition comprising platinum.
 29. Themethod of claim 18 wherein the slowing of the expansion of the cancercell comprises killing the cancer cell.